Therapeutic nasal spray administered composition containing feverfew

ABSTRACT

A composition and delivery system are disclosed that will allow feverfew to be administered to a person in form in which an active ingredient of feverfew, particularly parthenolide can be readily and quickly assimilated by the person&#39;s body, particularly the central nervous system, and the therapeutic effects of the feverfew be rapidly imparted to the person. Feverfew is administered in the form of aqueous nasal spray composition, to provide therapeutic moisturization of nasal mucous membranes, relief of migraine headaches and antispasmodic effect, such as to relieve menstrual cramping or aid digestion. The effect is enhanced when the composition also contains nanoclustered resonant water. Vitamins, vitamin derivatives, surfactants, wetting agents, preservatives and emulsifiers may also be present.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention herein relates to therapeutic medications. Moreparticularly it relates to therapeutic nasal sprays.

2. Description of the Prior Art

Feverfew (Tanacetum parthenium) is an herb in the Compositae familywhich has long been known to have therapeutic properties; see Bremness,(ed.), HERBS (1990), pp. 91, 185-186 and Castleman, THE HEALING HERBS(1991), pp. 173-176. At various times feverfew has been considered tohave therapeutic properties for reducing high blood pressure, acting asa digestive tract antispasmodic, relieving menstrual cramps and, mostimportantly, relieving migraine headaches. It has been administered asthe raw feverfew leaf, either fresh or frozen, which is taken by chewingor by swallowing pills or capsules in which the feverfew isincorporated. It has also been administered as a tea with aconcentration of 0.5-1 teaspoonfuls of feverfew per cup of boilingwater, and which is drunk after the tea has steeped for 5-10 minutes.

Such delivery systems have had significant problems. Raw feverfew leavesare bitter and therefore unpleasant to chew and the tea is unpleasant todrink. It has also been documented that raw feverfew leaves can causeoral ulcers or other irritation to the buccal membranes or mucous liningof the mouth. Therefore, when leaves are to be chewed, it has beenrecommended that they be chewed in combination with a larger quantity ofan innocuous foodstuff, commonly slices of bread. The general use offeverfew in the form of capsules or pills has been an attempt to avoidthe buccal irritation and ulcers and the bitter taste of the herb.

Administration of feverfew by swallowing of the chewed material,drinking of tea, or swallowing of capsules and pills means that thefeverfew [and its apparent active ingredient, parthenolide; see TheBurton Goldberg Group, (eds.), ALTERNATIVE MEDICINE; THE DEFINITIVEGUIDE (1995), p. 264] must be released and dispersed to the centralnervous system or other affected organs through the gastrointestinalsystem. Such administration is slow and relatively inefficient.Consequently, the therapeutic effects of feverfew will not be quicklyavailable to the person to whom the herb has been administered. This hasbeen particularly significant in the treatment of migraine headaches.The severe effects of migraine headache on a person have beenextensively and frequently documented, and delayed relief unnecessarilyextends the period of the sufferer's discomfort.

Nasal sprays have heretofore been commercially available formoisturization of the nasal membranes. Such sprays normally are watercontaining surfactants to spread the water over the nasal membranes andenhance the penetration of the water into the surface layers of themembranes. There is no therapeutic function of the water penetration.

Nasal sprays or drops have also been known for relief of migraineheadache, using conventional chemicals. For instance, nasal sprays ordrops containing dihydroergotamine, sumatriptan succinate or lidocainehave variously been reported, used commercially or usedinvestigationally.

Clustered water (or nanocluster resonant water) is the name given towater molecules associated in a unique physical structure. Variousembodiments of clustered water have been identified in recent years.They can be artificially produced by subjecting quantities of water tostrong magnetic fields; see, for instance, Lorenzen, NANOCLUSTEREDSOLUTIONS AS A SUPPORT BASE TO OPTIMIZE COHERENT CELLULAR COMMUNICATION(1995). Clustered water samples have been shown by NMR spectroscopy andother types of analyses to have different freezing points, pH levels,surface tensions and electrical conductivity values than conventionaldistilled tap or colloidal water. In cellular organic systems it isbelieved that the presence of clustered water will alter cellularresonance and influence internal chemical and enzymatic reactions. Thewater clusters can be directed to bind to pharmacological activesubstances and thus enhance the pharmacological activity of suchsubstances in cells.

SUMMARY OF THE INVENTION

There is a significant need for a delivery system that will allowfeverfew to be administered to a person in a form in which an activeingredient of feverfew can be readily and quickly assimilated by theperson's body, particularly the central nervous system, and thetherapeutic effects of the feverfew be rapidly imparted to the person.Further, enhancement of the therapeutic effects of feverfew by asynergistic agent will permit lower dosages of feverfew to be effectivetherapeutic agents while reducing the incidence of undesirable sideeffects such as buccal membrane irritation or ulceration. Thesetherapeutic effects are of particular benefit to sufferers of migraineheadaches. In addition, feverfew provides significant antispasmodiceffect, which can benefit a wide range of users, from women with thediscomfort of menstrual cramping to those persons suffering digestivedisorders involving intestinal spasms. With the compositions, methodsand products of this invention, the relief imparted by the feverfew willbe administered to the affected organs and systems of the body much morequickly than is possible through the prior art gastrointestinal systemadministration, and therefore migraine headaches and the discomforts ofinternal spasmodic cramping will be quickly and effectively alleviated.

We have discovered that by administering feverfew in the form of a nasalspray composed of an aqueous-based liquid and in which a smallconcentration of feverfew is dispersed or dissolved, the feverfew can beexpeditiously administered without undue irritation of the nasal mucousmembranes and acts rapidly and therapeutically to provide mucousmembrane moisturization relief of migraine headaches and provides anantispasmodic effect resulting in relief of menstrual cramping and inaid to digestion. The effect is enhanced when the aqueous mediumcontains a portion of nanoclustered resonant water, particularly whenthe aqueous medium is also saline.

In broad definitions of the various aspects of the present invention, itincludes a composition comprising an aqueous medium having incorporatedtherein a quantity of feverfew sufficient to provide at least atherapeutic moisturizing effect on nasal mucous membranes of a humanuser; a composition wherein the quantity of feverfew is sufficient tohave a therapeutic effect of relief of migraine headache suffered by ahuman user; or a composition wherein the quantity of feverfew issufficient to have a therapeutic antispasmodic effect on internal organsof a human user, such as the gastrointestinal system and the femalereproductive system.

Similarly, other broad definitions of the various aspects of the presentinvention include a nasal spray comprising an aqueous medium havingincorporated therein a quantity of feverfew sufficient to provide atleast a therapeutic moisturizing effect on nasal mucous membranes of ahuman user; a nasal spray wherein the quantity of feverfew is sufficientto have a therapeutic effect of relief of migraine headache suffered bya human user; or a nasal spray wherein the quantity of feverfew issufficient to have a therapeutic antispasmodic effect on internal organsof a human user, such as the gastrointestinal system and the femalereproductive system.

In yet other broad definitions, the various aspects of the presentinvention include a composition comprising an aqueous medium havingincorporated therein a quantity of parthenolide sufficient to provide atleast a therapeutic moisturizing effect on nasal mucous membranes of ahuman user; a composition as wherein said quantity of parthenolide issufficient to have a therapeutic effect of relief of migraine headachesuffered by a human user; or a composition wherein said quantity ofparthenolide is sufficient to have a therapeutic antispasmodic effect oninternal organs of a human user, such as the gastrointestinal system andthe female reproductive system.

Further broad definitions of the various aspects of the presentinvention include a method of relieving the physical effects of nasaldryness or irritation in a human by administration into a nasal cavityof the human a spray composition comprising an aqueous medium havingincorporated therein a quantity of feverfew sufficient to provide atleast a therapeutic moisturizing effect on nasal mucous membranes withinthe nasal cavity; a method of relieving the physical effects of migraineheadache in a human by administration into a nasal cavity of the human aspray composition comprising an aqueous medium having incorporatedtherein a quantity of feverfew sufficient to have a therapeutic effectof relief of migraine headache suffered by the human; or a method ofproviding an antispasmodic effect to internal organs in a human byadministration into a nasal cavity of the human a spray compositioncomprising an aqueous medium having incorporated therein a quantity offeverfew sufficient to have an antispasmodic therapeutic effect on saidorgans and thereby serving as a digestive aid for the human or providingrelief of cramping or related spasm-associated effects suffered by thehuman.

The therapeutic effects of the present invention's compositions andmethods can be enhanced by incorporation into the aqueous medium of aquantity of "clustered water," i.e., non-clustered resonant water. Themedium may be saline and may also include vitamins, vitamin derivatives,surfactants, wetting agents, preservatives and emulsifiers.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

The crux of the present invention is our discovery that feverfew can beadministered as a nasal spray and thus acts as an effective therapeuticagent without undesirable side effects and in a form palatable andtolerable to users. The nasal spray is in the form of a dilute aqueoussolution or suspension of finely divided pieces of feverfew leaf.

Nasal administration of feverfew has never previously been describednor, to our knowledge, even considered as potentially effective. Alladministration of feverfew in the past, stretching back many years, hasbeen for oral administration and delivery through the gastrointestinaltract, with strong emphasis that residence in the oral cavity must beminimal and must be tempered or buffered in some manner to counteractthe known irritant and ulcerative properties of feverfew. Indeed, themodern incorporation of feverfew into pills or capsules which passintact through the oral cavity and reach the gastrointestinal systemwithout any release of feverfew represents complete confinement offeverfew for delivery through the gastrointestinal tract.

We have discovered, however, that the unique nasal spray administrationmethod described herein is surprisingly effective in providing rapidassimilation and resulting therapeutic effect of the feverfew, bydelivery through the nasal mucous membranes into the central nervoussystem.

Feverfew is an herb of the Compositae family. It has been known anddescribed for many years by various herbalists, and is commonly used fordecorative purposes because of its attractive leaves and flowers. Thereare several subspecies of feverfew, including golden feverfew, doublefeverfew, and american feverfew. As is further disclosed herein,feverfew has also been known or believed to have certain therapeuticeffects on humans.

In the present invention, feverfew is provided by either by pickingfresh leaves and allowing them to dry to a stage where they can befinely ground or otherwise comminuted, or by obtaining previously driedleaves, preferable already ground to the desired size. The dried leafparticles are dispersed or dissolved in an aqueous media, which may bepure water or water with various emulsifying agents, surfactants orother feverfew-compatible additives in it. The ground particle size foreffective dissolution or dispersion is on the order of approximately0.1-20 μm, more preferably 0.2-10 μm, and most preferable on the orderof about 0.2-5 μm. Incorporation of the feverfew into the aqueouscarrier may be aided by first dispersing the feverfew as a 4%concentration in a lactone solution. When thoroughly mixed and dispersedand/or dissolved, the feverfew will commonly be present at aconcentration level in the aqueous carrier on the order of 0.001-2.0%,more preferably 0.01-0.35%, with a particularly preferred concentrationon the order of about 0.10%. (All percentages herein are by weightunless otherwise noted.)

In preferred embodiments, the nasal spray composition will also have asmall amount of nanoclustered resonant water present. This mayconveniently be provided in the form of a clustered water bufferingsystem which includes a borate buffer. The presence of the clusteredwater borate buffering system serves to enhance the therapeutic effectsof the feverfew. It also is believed to stimulate the membrane cells andenhance the moisturizing effect of the aqueous medium on the nasalmembranes. In the buffering system, the clustered water is formulatedusing a magnetic resonance process of the type described by Lorenzen.The clustered water remains chemically identical with the unprocessedwater in the aqueous carrier, but when exposed to biological molecules,i.e., those making up the user's nasal system and nasal mucousmembranes, the clusters form complexes that are believed to take on astructural and electronic signature of biomolecules and thus enhance thebiological effectiveness of the nasal spray and of the therapeuticdelivery of the feverfew.

Specifically, the clustered water is formed by using a novel processwhich is the subject of a co-pending patent application in the name ofco-inventor Lorenzen. In this process highly distilled water is exposedto fluctuations in temperature ranging from -6° C. to 110° C. andelectromagnetic fields ranging in power density in the range of 0.7-28Tesla while being pumped through a ceramic coated baffle for a period ofup to 24 hours. As no ceramic materials are transferred to the waterduring this process, the resulting solution meets or exceeds U.S. patentstandards for "pure water." Further treatment with a tunable diode laser(50 watt) is used to induce the formation of water molecules intopentagonal, hexagonal and/or heptagonal ring structures. When thesolution has reached the minimum target ring density of about 23% it isblended with the other nasal spray ingredients. Conveniently it is inthe form of a borate buffer, which is present in a concentration in therange of 0.01-1.0%, preferably 0.05-0.50%, and more preferably on theorder of about 0.10%. The ring structures improve the solubility of theother ingredients and enhance the bioactivity and membrane transfereffects of the product.

As noted, various other materials may also advantageously be present inthe nasal spray in appropriate quantities. It is preferred to make thesolution mildly saline, by dissolving a small amount of sodium chloridein the aqueous medium. The salt concentration may be in the range of0.1-2.0% and will preferably be on the order of about 0.65%.

Other materials such as surfactants, vitamins and vitamin derivatives,antihistamines, wetting agents, preservatives, moisturizers,emulsifiers, odorants and the like may also be present in conventionalconcentrations. There are numerous disclosures of suitable materials inthe literature, along with descriptions of efficacious concentrations inaqueous media. Those skilled in the art will have no difficulty indetermining suitable materials and concentrations for their knownfunctions.

Delivery of the spray to the nasal cavity may be by any conventionalspray technique or device. Spray administration containers for varioustypes of nasal sprays have been known in the past and substantially allwill be equally suitable for the present invention, considering ofcourse that the materials from which the container is made must becompatible with the spray composition. The aqueous liquid mediumcontaining the feverfew, clustered water and other appropriateingredients will commonly be contained in a small bottle or similarcontainer with a focused nozzle, from which it can be dispersed as afine mist to be directed into each nostril. Using ambient air as thepropelling agent, one can have the bottle made of a flexible plastic, sothat merely squeezing the bottle's sides impels the spray out throughthe nozzle into the nasal cavity. Air is also the propelling agent for apump sprayer, in which the user manipulates a small pump button whichpumps air into the container and causes the liquid spray to be emittedon the return stroke. Alternatively, the bottle can be pressurized witha gas which is inert to the user and to the ingredients of the solution.The gas will be dissolved under pressure in the container or may begenerated by dissolution or reaction of a solid material which forms thegas as a product of dissolution or as a reaction product. Typical gaseswhich can be used include nitrogen, argon, and carbon dioxide.

It is contemplated that the user will spray two or three sprays in eachnostril at each administration, with the administration being repeatedon an as needed basis. The frequency of administration will be dependenton the nature of the usage. If administration is for relief of a currentcondition, such as a current migraine headache, initial relief effectscan be expected within a few minutes of administration. If such does notoccur, the user may administer a second dosage. Dosages may be repeatedat intervals as the effect wears off, if the headache persists. The userwill normally discontinue administration once the headache has subsided.Administration can be resumed at a subsequent time when another headacheoccurs. It is also contemplated that the nasal spray can be administeredregularly in smaller doses and on a less frequent basis, to create aprophylactic effect intended to prevent the onset of migraine headaches,menstrual cramps, intestinal spasms, or the like, or to serve as adietary aid. It is recommended that the spray not be used by pregnantwomen, as there may be a small possibility that the feverfew maystimulate the uterus. Delivery rates will usually be on the order ofabout 50-100 μl per spray.

The composition will be seen to be useful for a number of differentkinds of therapeutic uses. At its most basic level, the nasal sprayserves as a moisturizer for the nasal mucous membranes, providing asoothing and moistening effect which alleviates the effects of dryness,wind, dust and other irritants on the nasal membranes.

At another level, and preferred for the present invention, thecompositions of the present invention administered through the nasalspray serve as rapid and efficient therapeutic agents for relief ofmigraine headaches. The manner in which the feverfew component serves toalleviate migraine headaches has been the subject of a number ofstudies. It is believed that the effect primarily rises from thepresence of parthenolide in the feverfew leaf. When application of thefeverfew through the nasal spray is terminated, the migraine headachemay return unless the causal conditions have in the meantime changed orthemselves terminated. However, since for most sufferers migraineheadaches rarely continue for more than a few hours or at most a fewdays, limited use of the feverfew nasal spray of the present inventionover the appropriate period will be highly effective in suppressing thepain and other undesirable effects of the migraine headache for a periodsufficient for the migraine-causing conditions to be eliminated by thenatural processes of the body.

In yet another embodiment the application of the nasal spray of thepresent invention can provide an antispasmodic effect to internal organswhich are subject to spasm under various conditions. For instance,shortly prior to and during menstruation, many women suffer crampingrelated to spasmodic reactions of the female reproductive organs, whichmay be relieved by administration of the present nasal spray during thistime. Similarly, spasmodic reactions of the gastrointestinal systems canimpair digestive function and cause intestinal discomfort to manypeople. The nasal spray may be used to aid digestion by acting as anantispasmodic and thus calm the smooth muscles of the digestive tract.Administration after meals if discomfort is experienced may provebeneficial. Since limited time periods are normally involved in bothinstances, repeated use of the nasal spray of the present invention onan as-needed basis is not anticipated to cause any significant problems.Once the immediate cramping or discomfort subsides, the user willnormally discontinue application of the spray. Its use can be resumed ifthe cramping or discomfort reoccurs at a later time.

The following composition is an example of a typical efficacious nasalspray composition of the present invention.

    ______________________________________                                        Ingredient             Content                                                ______________________________________                                        feverfew (4% lactone)  0.10%                                                  clustered water borate buffer                                                                        0.10%                                                  NaCl                   0.65%                                                  ascorbic acid derivative.sup.1                                                                       0.20%                                                  polyoxyethylene (20) sorbitan monooleate.sup.2                                                       0.13%                                                  goldenseal.sup.3       0.05%                                                  benzalkonium chloride  0.03%                                                  ethylenediamine tetraacetic acid                                                                      0.025%                                                water                  Balance                                                ______________________________________                                         .sup.1 "Ester C" esterified commercial product                                .sup.2 "Polysorbate 80" commercial product                                    .sup.3 Hydrastis canadensis, of the Ranunculaceae family                 

It will be evident that there are numerous embodiments of the presentinvention, which, while not expressly set forth above, are clearlywithin the scope and spirit of the present invention. The abovedescription is therefore intended to be exemplary only, and theinvention is to be limited solely by the appended claims.

We claim:
 1. A composition for nasal administration to a human usercomprising a sprayable aqueous medium having dispersed or dissolvedtherein feverfew dried leaf particles having a particle size on theorder of 0.1-2.0 μm, said feverfew being present in a concentration onthe order of 0.001-2.0% in said aqueous medium and effective whenadministered as a spray to said human user's nasal mucous membranes toprovide to said human user a therapeutic effect selected from the groupconsisting of a moisturizing effect on nasal mucous membranes of saidhuman user, relief of migraine headache suffered by said human user, andan antispasmodic effect on internal organs of said human user.
 2. Acomposition as in claim 1 wherein said quantity of feverfew is effectiveto have a therapeutic effect of relief of migraine headache suffered bysaid human user.
 3. A composition as in claim 1 wherein said quantity offeverfew is effective to have an antispasmodic therapeutic effect oninternal organs of said human user.
 4. A composition as in any of claims1, 2 or 3 wherein said feverfew is present in a concentration in therange of 0.01% to 0.35%.
 5. A composition as in claim 4 wherein saidfeverfew is present in said aqueous medium in a concentration in on theorder of 0.10%.
 6. A composition as in any one of claims 1, 2 or 3wherein said aqueous medium comprises clustered water.
 7. A compositionas in claim 5 wherein said clustered water is present in the form of aborate buffer dispersed in said aqueous medium.
 8. A composition as inclaim 7 wherein said buffer is present in said aqueous medium in aconcentration in the range of 0.01-1.0%.
 9. A composition as in claim 8wherein said buffer is present in said aqueous medium in a concentrationin the range of 0.05-0.50%.
 10. A composition as in claim 9 wherein saidbuffer is present in said aqueous medium in a concentration on the orderof 0.10%.
 11. A composition as in any one of claims 1, 2 or 3 whereinsaid aqueous liquid is saline.
 12. A composition as in any one of claims1, 2 or 3 further comprising a material selected from the groupconsisting of surfactants, vitamins, vitamin derivatives, wettingagents, preservatives and emulsifiers.
 13. A composition as in any oneof claims 1 or 3 wherein internal organs which are affected by saidantispasmodic effect are the gastrointestinal organs or the femalereproductive organs.
 14. A nasal spray for nasal administration to ahuman user comprising a sprayable aqueous medium having dispersed ordissolved therein feverfew dried leaf particles having a particle sizeon the order of 0.1-2.0 μm, said feverfew being present in aconcentration on the order of 0.001-2.0% in said aqueous medium andeffective when administered as a spray to said human user's nasal mucousmembranes to provide to said human user a therapeutic effect selectedfrom the group consisting of a moisturizing effect on nasal mucousmembranes of said human user, relief of migraine headache suffered bysaid human user, and an antispasmodic effect on internal organs of saidhuman user.
 15. A nasal spray as in claim 14 wherein said quantity offeverfew is effective to have a therapeutic effect of relief of migraineheadache suffered by said human user.
 16. A nasal spray as in claim 14wherein said quantity of feverfew is effective to have an antispasmodictherapeutic effect on internal organs of said human user.
 17. A nasalspray as in any of claims 14, 15 or 16 wherein said feverfew is presentin a concentration in the range of 0.01% to 0.35%.
 18. A nasal spray asin claim 17 wherein said feverfew is present in a concentration on theorder of 0.10%.
 19. A nasal spray as in any one of claims 14, 15 or 16wherein said aqueous medium comprises clustered water.
 20. A nasal sprayas in claim 19 wherein said clustered water is present in the form of aborate buffer dispersed in said aqueous medium.
 21. A nasal spray as inclaim 20 wherein said buffer is present in said aqueous medium in aconcentration in the range of 0.01-1.0%.
 22. A nasal spray as in claim21 wherein said buffer is present in said aqueous medium in aconcentration in the range of 0.05-0.50%.
 23. A nasal spray as in claim22 wherein said buffer is present in said aqueous medium in aconcentration on the order of 0.10%.
 24. A nasal spray as in any one ofclaims 14, 15 or 16 wherein said aqueous liquid is saline.
 25. A nasalspray as in any one of claims 14, 15 or 16 further comprising a materialselected from the group consisting of surfactants, vitamins, vitaminderivatives, wetting agents, preservatives and emulsifiers.
 26. A nasalspray as in any one of claims 14 or 16 wherein internal organs which areaffected by said antispasmodic effect are the gastrointestinal organs orthe female reproductive organs.
 27. A composition comprising a sprayableaqueous medium having dispersed or dissolved therein parthenolideincorporated in feverfew dried leaf particles having a particle size onthe order of 0.1-2.0 μm, said feverfew particles being present in aconcentration on the order of 0.001-2.0% in said aqueous medium andeffective when administered as a spray to said human user's nasal mucousmembranes to provide to said human user a therapeutic effect selectedfrom the group consisting of a moisturizing effect on nasal mucousmembranes of said human user, relief of migraine headache suffered bysaid human user, and an antispasmodic effect on internal organs of saidhuman user.
 28. A composition as in claim 27 wherein said quantity ofparthenolide is effective to have a therapeutic effect of relief ofmigraine headache suffered by a human user.
 29. A composition as inclaim 27 wherein said quantity of parthenolide is effective to have anantispasmodic therapeutic effect on internal organs of said human user.30. A composition as in any of claims 27, 28 or 29 wherein saidparthenolide is present in a concentration in the range of 0.01% to0.35%.
 31. A composition as in claim 30 wherein said parthenolide ispresent in said aqueous medium in a concentration in on the order of0.10%.
 32. A composition as in any one of claims 27, 28 or 29 whereinsaid aqueous medium comprises clustered water.
 33. A composition as inclaim 32 wherein said clustered water is present in the form of a boratebuffer dispersed in said aqueous medium.
 34. A composition as in claim33 wherein said buffer is present in said aqueous medium in aconcentration in the range of 0.01% to 1.0%.
 35. A composition as inclaim 34 wherein said buffer is present in a concentration in the rangeof 0.05% to 0.50%.
 36. A composition as in claim 35 wherein said bufferis present in a concentration on the order of 0.10%.
 37. A compositionas in any one of claims 27, 28 or 29 wherein said aqueous liquid issaline.
 38. A composition as in any one of claims 27, 28 or 29 furthercomprising a material selected from the group consisting of surfactants,vitamins, vitamin derivatives, wetting agents, preservatives andemulsifiers.
 39. A composition as in any one of claims 27 or 29 whereininternal organs which are affected by said antispasmodic effect are thegastrointestinal organs or the female reproductive organs.